DE1914016C - Process for the preparation of 4,5 benz isothiazol 3 on 1 oxyden - Google Patents
Process for the preparation of 4,5 benz isothiazol 3 on 1 oxydenInfo
- Publication number
- DE1914016C DE1914016C DE1914016C DE 1914016 C DE1914016 C DE 1914016C DE 1914016 C DE1914016 C DE 1914016C
- Authority
- DE
- Germany
- Prior art keywords
- acid
- hydrogen
- preparation
- oxyden
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title description 2
- WMUFLFBYCPACRG-UHFFFAOYSA-N cyclopenta[e]thiazine Chemical compound C1=NSC2=CC=CC2=C1 WMUFLFBYCPACRG-UHFFFAOYSA-N 0.000 title 1
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- -1 halogen amines Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 1
- 229920001296 polysiloxane Polymers 0.000 claims 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 102100019312 CACTIN Human genes 0.000 description 1
- 108010065235 Drosophila cactin protein Proteins 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N Hydrazoic acid Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N Potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- NOTVAPJNGZMVSD-UHFFFAOYSA-N Potassium oxide Chemical compound [K]O[K] NOTVAPJNGZMVSD-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N Sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- GYMBTLRVABDEHT-UHFFFAOYSA-N chlorobenzene;dichloromethane Chemical compound ClCCl.ClC1=CC=CC=C1 GYMBTLRVABDEHT-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910001392 phosphorus oxide Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
Description
4,5-lkiizi,sutliiuzol-3-on-l-oxyUu dor allgemeinen Formel I4,5-lkiizi, sutliiuzol-3-on-l-oxyUu dor general Formula I.
von 250 mft'k» cino durchsehniltliclw Abnahme des 'DliitziickgrBehulies von 12%.from 250 mft'k »cino durchehniltliclw decrease of the 'Dliitzggbehulies of 12%.
worin R1 niedermolekulare Alkylgruppen, wie Methyl-, Äthyl-, Propyl- und Butylreste, oder den Phenylrcsl, R2 und R-1 Wasserstoff- oder Halogenamine bedeuten, werden dadurch hergestellt, daß man Sulfoxyde der allgemeinen Formel II,wherein R 1 low molecular weight alkyl groups, such as methyl, ethyl, propyl and butyl radicals, or the phenyl radicals, R 2 and R -1 are hydrogen or halogen amines, are prepared by using sulfoxides of the general formula II,
IlIl
worin R4 ein Wassersloffalom oder eine niedermolc- jo kuhirc Alkylgruppe darstellt, in Gegenwart starker anorganischer Säuren, wie Schwefelsäure, Phosphorsäure oder Polyphosphorsäure, vorzugsweise, jedoch Polyphosphorsäure. gegebenenfalls unter Zusatz eines inerten und mit Wasser nicht mischbaren Lösungsmittels, wie Bcn/ol, Toluol, Chlorbenzol und Diehloräthan, bei 60 bis 120 C. vorzugsweise bei 80 bis 100 C, mit Stickstoffwasserstoffsäure oderderen Salzen reagieren lal.it und anschließend das Reaktionsprodukt I isoliert.where R 4 is a hydrogen sulfide or a niedermolc- jo kuhirc alkyl group, in the presence of strong inorganic acids such as sulfuric acid, phosphoric acid or polyphosphoric acid, but preferably polyphosphoric acid. optionally with the addition of an inert and water-immiscible solvent, such as benzene, toluene, chlorobenzene and diehloroethane, at 60 to 120 ° C., preferably at 80 to 100 ° C., react with hydrazoic acid or its salts and then the reaction product I is isolated .
Die Verbindungen 1 stellen wertvolle Ausgangsprodukte zur Darstellung neuartiger Arzneimittel dar. Die neuen Verbindungen besitzen eine blutziickersenkende und kranipliöseiule Wirkung und schützen vor ilen Folgen des Fleklroschocks. \$ The compounds 1 are valuable starting products for the preparation of novel medicaments. The new compounds have a blood-hypoglycemic and cranial effect and protect against the ile consequences of fleece shock. \ $
H e i s ρ i e I I
. l-MethyW.s-henzisolhiazol-.i-on-l-oxydH eis ρ ie II
. l-MethyW.s-henzisolhiazol-.i-on-l-oxide
In ein (icmisch aus SOOg 85%iger Phosphorsäure und 250 g Phosphorpcnloxyd trägt man W g(0,5 Mol) 2-Melhyl-sulfinylbenzoesäure-meihylesler oder ()2 g (0,5 MoI) 2-Methyl-sullin>lben/oesiiure ein und erwärmt auf XOC. Hei dieser Temperatur verselzl man unter kräftigem Ruinen inv Verlauf von 2 Stunden portionsweise mit .V) g (0,0 Mol) Natriuma/id bzw. 4l) g (0,6 Mol) Kaliuma/id. Nach beendeter Zugabe rührt man noch 4 Sluiideii bei der gleichen Temperatur, kiihll ab und verdünnt mit 500 ml Wasser. Danach neutralisiert man das (icmisch mit wäßriger Kalilauge und saugt das Kcaktinnsprodukl ab. Umkristallisieren aus Wasser liefert 77 g (85% der Theorie) farblose Krislalle. Schinp. 210 bis 211 C. W g (0.5 mol) of 2-methylsulfinylbenzoic acid methylene or ( ) 2 g (0.5 mol) of 2-methylsulline are added to a mixture of 50% phosphoric acid and 250 g of phosphorus oxide. oesic acid and warmed to XOC. At this temperature, under vigorous ruins, in the course of 2 hours in portions with .V) g (0.0 mol) sodium oxide or 4 l ) g (0.6 mol) potassium oxide . When the addition is complete, stir 4 more slides at the same temperature, cool and dilute with 500 ml of water. The mixture is then neutralized with aqueous potassium hydroxide solution and the cactin product is filtered off with suction. Recrystallization from water gives 77 g (85% of theory) of colorless crystals. Schinp. 210 to 211 C.
Die Substanz bewirkt an 12 männlichen oder weiblichen
Kaninchen (Tiere, welche für diese Teslarl besonders geeignet sind) bei peroraler Applikation
Beispiel 2
I -(n-Butyl)-4,5-benz.isolhiiizol-.l-on-l -oxydThe substance effects example 2 on peroral application in 12 male or female rabbits (animals which are particularly suitable for this Teslarl)
I - (n-butyl) -4,5-benz.isolhiiizol-.l-one-l -oxide
ίο Die Darstellung erfolgt, wie im Beispiel I angegeben, aus 0,1 Mol ^-(n-Bulyl-siiirmyD-benz.oesiiuremelhylester mit 0,12 Mol Nalriuinazid oder Kaliuniazid in Polyphosphorsäure bei 80 C. Aus Wasser Äthanol (70: .10) erhält man farblose Kristalle. Schmp.ίο The representation takes place as indicated in example I, from 0.1 mol of ^ - (n-Bulyl-siiirmyD-benz.oesiiuremelhylester with 0.12 moles of sodium azide or potassium uniazide in polyphosphoric acid at 80 ° C. Colorless crystals are obtained from water, ethanol (70: 10). M.p.
is If) C. is If) C.
Beispiel .1
5-chlor-l-melhyl-4,5-benzisolhiazol-.l-on-l-o\ydExample 1
5-chloro-1-methyl-4,5-benzisole-thiazol-.l-on-lo \ yd
Die Darstellung erfolgt aus 0,1 Mol 5-Chlor-2-me-The representation is made from 0.1 mol of 5-chloro-2-me-
thyl-sulfmylhenzoesäure-methylesler und 0.12 Molthyl-sulfmylhenzoic acid methyl ester and 0.12 mol
Natriumazid wie im Beispiel 1 angegeben. Aus Älhanol Wasser (1:1) erhält man farblose Kristalle vom Schmelzpunkt ll'4 C.Sodium azide as indicated in Example 1. From Älhanol water (1: 1) gives colorless crystals of melting point l l '4 C.
Beispiel 4
5,7-Dichlor-l-methyl-4,5-benzisolhiazol-.l-on-l-oxydExample 4
5,7-dichloro-1-methyl-4,5-benzisole-thiazol-.l-one-l-oxide
18 g l,5-Dichlor-2-(melhyl-sulTmyl)-benzoesäuremelhylester werden mit 6 g Nalriuinazid in Polyphosphorsäure hei HO C gemäß Beispiel 1 umgesetzt. Farblose Krislalle; Schmp. 215 C (aus Uopropanol).18 g of 1,5-dichloro-2- (methyl-sulfyl) -benzoic acid methyl ester are reacted with 6 g of sodium azide in polyphosphoric acid hot HO C according to Example 1. Colorless crystals; Mp. 215 ° C. (from uropropanol).
Beispiel 5
l-I'henyl-U-benzisothiazol-.l-on-l oxydExample 5
l-I'henyl-U-benzisothiazol-.l-one-loxide
0,05 Mol 2-(Phenvl-suliinyl)-k-nzoes;iUK iiielhylester werden in 100 ml C'hlorbenzol gelost und zu einem (icmisch aus .10 g H5%iger Phosphorsäure und 15 g PhosphorpentiHvd gegeben. Bei 100 C trägt man unter Rühren portionsweise 0,07 Mol Natriumazid oder Kaliuinazid ein und rührt anschließend noch 16 Stunden lvi dieser Temperatur. Nach dem Abkühlen verdünnt man mit Wasser und trennt das Chloibenzol ab Die wäßrige Phase wird mit Kalilauge neutralisier! und mit Dichlormcthan ausgeschüttelt. Nach dem Trocknen und Finengen der vereinigten DichlonnethanChlorbenzol-l osung kristallisiert man den Rückstand aus Fssigsäureäthylester Diisopropylälher um. Schmp. 127 bis 128 C0.05 moles of 2- (phenyl-suliinyl) -k-nzoes; iUK iiielhyl ester are dissolved in 100 ml of chlorobenzene and mixed with 10 g of H5% phosphoric acid and given 15 g of PhosphorpentiHvd. At 100 C 0.07 mol of sodium azide or potassium azide are added in portions with stirring and then stirred 16 hours at this temperature. After cooling, it is diluted with water and separates the chloibenzene from the aqueous phase neutralize with potassium hydroxide! and shaken out with dichloromethane. After drying and fining the combined dichloromethane-chlorobenzene solution the residue is recrystallized from Fssigsäureäthylester Diisopropylälher. M.p. 127 to 128 C
Die Substanz bewahrt bei peroraler Applikation an 12 Mäusen in einer Dosis von 100 mg, kg Körpergewicht alle Tiere vor den Wiikiiiuicn des Fleklroschocks. When administered orally to 12 mice, the substance is preserved in a dose of 100 mg, kg of body weight all animals before the Wiikiiiuicn of the Fleklroshock.
Im ('ardiazolkrampfvciMich erhält man folgende Resullale:In ('ardiazolkrampfvciMich one obtains the following Resullale:
5050
Konirolle (Traganlhschleim)
75 mg/kg l-Phenyl-4,5-beiizisi>thiazol-.l-oxo-l-oxyd
Konirolle (Traganlhschleim)
75 mg / kg of l-phenyl-4,5-azizisi> thiazole-.l-oxo-l-oxide
Ii.-ii·Ii.-ii ·
Iu-U; milIu-U; mil
Stii-ik-Stii-ik-
k 1.1 ιηρΙιΊΐk 1.1 ιηρΙιΊΐ
Claims (2)
Family
ID=
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